The EPIC-Norfolk Study
Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
Journal of the American College of Cardiology 2013 ; 62: 1966-1976.
Holmes MV, Simon T, Exeter HJ, Folkersen L, Asselbergs FW, Guardiola M, Cooper JA, Palmen J, Hubacek JA, Carruthers KF, Horne BD, Brunisholz KD, Mega JL, van Iperen EPA, Li M, Leusink M, Trompet S, Verschuren JJW, Hovingh GK, Dehghan A, Nelson CP, Kotti S, Danchin N, Scholz M, Haase CL, Rothenbacher D, Swerdlow DI, Kuchenbaecker KB, Staines-Urias E, Goel A, van 't Hooft F, Gertow K, de Faire U, Panayiotou AG, Tremoli E, Baldassarre D, Veglia F, Holdt LM, Beutner F, Gansevoort RT, Navis GJ, Mateo Leach I, Breitling LP, Brenner H, Thiery J, Dallmeier D, Franco-Cereceda A, Boer JMA, Stephens JW, Hofker MH, Tedgui A, Hofman A, Uitterlinden AG, Adamkova V, Pitha J, Onland-Moret NC, Cramer MJ, Nathoe HM, Spiering W, Klungel OH, Kumari M, Whincup PH, Morrow DA, Braund PS, Hall AS, Olsson AG, Doevendans PA, Trip MD, Tobin MD, Hamsten A, Watkins H, Koenig W, Nicolaides AN, Teupser D, Day INM, Carlquist JF, Gaunt TR, Ford I, Sattar N, Tsimikas S, Schwartz GG, Lawlor DA, Morris RW, Sandhu MS, Poledne R, Maitland-van der Zee AH, Khaw KT, Keating BJ, van der Harst P, Price JF, Mehta SR, Yusuf S, Witteman JCM, Franco OH, Jukema JW, de Knijff P, Tybjaerg-Hansen A, Rader DJ, Farrall M, Samani NJ, Kivimaki M, Fox KAA, Humphries SE, Anderson JL, Boekholdt SM, Palmer TM, Eriksson P, Pare G, Hingorani AD, Sabatine MS, Mallat Z, Casas JP, and Talmud PJ
DOI : 10.1016/j.jacc.2013.06.044
PubMed ID : 23916927
PMCID : PMC3826105
URL : https://linkinghub.elsevier.com/retrieve/pii/S0735109713027782
Abstract
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.
We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.
PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.
Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.